The liver is a multifunctional organ with roles in metabolism, detoxification, and the immune response. Liver secretory selenoprotein P (SeP), a hepatokine, causes insulin resistance in the liver and peripheral muscle. We showed hepatitis C virus (HCV) infection increased serum SeP levels, which may explain the increased risk of type 2 diabetes in patients with HCV infection. Increased SeP mRNA (SEPP1 mRNA) in hepatocytes inhibited type 1 interferon response by means of undefined unique mechanisms. We revealed SEPP1 mRNA directly bound to retinoic acidinducible gene I (RIG-I), a virus RNA sensor, and inhibited RIG-I activity. The robust induction of interferon-stimulated genes (>1000-fold) and repression of HCV replication (>10-fold) were observed in hepatocytes in which SEPP1 mRNA was knocked down. Clinically, high SeP serum levels were significantly associated with treatment failure of direct actingantivirals for HCV. Thus, SeP regulates insulin resistance and innate immunity, possibly inducing immune tolerance in the liver.
Murai, Kazuhisa and Honda, Masao and Shirasaki, Takayoshi and Shimakami, Tetsuro and Misu, Hirofumi and Kita, Yuki and Takeshita, Yumie and Takamura, Toshinari and Urabe, Takeshi and Shimizu, Ryogo and Okada, Hikari and Yamashita, Taro and Sakai, Yoshio and Kaneko, Shuichi, mRNA for Selenoprotein P, a Hepatokine, Binds RIG-I Protein and Inhibits the RIG-I-Mediated Type I Interferon Response (2018). Available at SSRN: https://ssrn.com/abstract=3155602 or http://dx.doi.org/10.2139/ssrn.3155602
This version of the paper has not been formally peer reviewed.
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